An efficient and convenient method for synthesis of 1-substituted imidazoles

Article abstract of DOI:10.3987/COM-06-10726

A convenient method for the synthesis 1-substituted imidazoles was developed by the reaction of α-bromoketone with lithium imidazolide. The reaction gave the desired products in improved yields without the formation of 1,3-disubstituted imidazolium salts. Treatment of bromoacetaldehyde ethylene acetal, 2-(bromomethyl)tetrahydro-2H-pyran, and N-(bromomethyl)phthalimide with lithium imidazolide also gave the corresponding 1-substituted imidazole in good to excellent yields. Direct reaction of α-bromoketone with imidazole as control experiment afforded undesired 1,3-disubstituted imidazolium salts with the desired mono-substituted products.

Full text of DOI:10.3987/COM-06-10726

HETEROCYCLES, Vol. 68, No. 7, 2006
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HETEROCYCLES, Vol. 68, No. 7, 2006, pp. 1359 - 1370. © The Japan Institute of Heterocyclic Chemistry
Received, 10th March, 2006, Accepted, 29th May, 2006, Published online, 30th May, 2006. COM-06-10726
AN EFFICIENT AND CONVENIENT METHOD FOR SYNTHESIS OF
1-SUBSTITUTED IMIDAZOLES
Chun Min Lin,c Fung Fuh Wong,＊,a,b Jiann-Jyh Huang,d and Mou-Yung
Yehc,e
aSustainable Environment Research Center, National Cheng Kung University, No.
500, Sec. 3, An-ming Rd., Tainan City, Taiwan 709, R.O.C.
bGraduate Institute of Pharmaceutical Chemistry, China Medical University, No.
91 Hsueh-Shih Rd. Taichung, Taiwan 40402, R.O.C.
cDepartment of Chemistry, National Cheng Kung University, No. 1, Ta Hsueh Rd.,
Tainan, Taiwan 70101, R.O.C.
dDevelopment Center for Biotechnology, No. 101, Lane 169, Kangning St., Xizhi
City, Taipei County, Taiwan 221, R.O.C.
eNan Jeon Institute of Technology, No.178, Chaocin Rd., Yanshuei Township,
Tainan County, Taiwan 737, R. O. C.
*Corresponding Author. Tel.: +886 6 384 0136 ext. 212; Fax.: +886 6 384 0960.
E-mail address: wongungfuh@yahoo.com.tw (F. F. Wong).
Abstract – A convenient method for the synthesis 1-substituted imidazoles was
developed by the reaction of α-bromoketone with lithium imidazolide. The
reaction gave the desired products in improved yields without the formation of
1,3-disubstituted imidazolium salts. Treatment of bromoacetaldehyde ethylene
acetal, 2-(bromomethyl)tetrahydro-2H-pyran, and N-(bromomethyl)phthalimide
with lithium imidazolide also gave the corresponding 1-substituted imidazole in
good to excellent yields. Direct reaction of α-bromoketone with imidazole as
control experiment afforded undesired 1,3-disubstituted imidazolium salts with
the desired mono-substituted products.
INTRODUCTION
The imidazole moiety is an important and frequent structural feature of many biologically active
compounds such as cytochrome P450 enzyme inhibitors1 and peptide analog inhibitors of human
immunodeficiency virus (HIV-1) protease.2 Most of imidazolode compounds are useful as drugs for

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HETEROCYCLES, Vol. 68, No. 7, 2006
treatment of many diseases, including cancer,3 acquired immune deficiency syndrome (AIDS)2 and also
as cholesterol lowering4 and antifungal agents. The steroids5 consisted of an imidazole moiety at C-21
position are also intensively investigated for some special biological activity.6,7 As a result, we planned to
develop a new method for the synthesis of 1-substituted imidazoles from the corresponding
α-bromoketone in improved yields without the formation of frequently observed 1,3-disubstituted
imidazolium salts.
Many methods have been developed to prepare the 1-substituted imidazoles (monosubstituted imidazoles).
Direct reaction of α-bromoketone with excess amount of imidazole8 is a common method. In some cases,
addition of a strong base or an acid catalyst was necessary.9 Thermal decarboxylation of
N-alkoxycarbonyl imidazoles10 and the 1-protected imidazoles, such as 1-trimethylsilyl, 1-acetyl,
1-benzoyl and 1-ethoxycarbonylimidazole, was also reported.11 Most of them could not provide
satisfactory results due to the formation of 1,3-disubstituted imidazolium salts. The purification of
1-substituted imidazole derivatives was thus troublesome, especially in large-scale preparation. As a
result, low isolated yields were the main disadvantage of these methods.
In this work, we reported an efficient and convenient method for the preparation of 1-substituted
imidazoles from lithium imidazolide and α-bromoketones. The formation of 1,3-disubstituted products
was not observed in this reaction. A control experiment was also performed by direct treatment of
imidazole with α-bromoketones for the comparison purpose.
RESULTS AND DISCUSSION
The newly developed method for the synthesis of 1-substituted imidazoles was shown in Scheme 1. The
preparation of lithium imidazolide was achieved by reaction of imidazole (3.0 equiv) in THF with lithium
hydride (3.1 equiv) at reflux. α-Bromoketone (1.0 equiv) was the added to the reaction mixture at –5~0
°C for the generation of 1-substituted imidazoles. After normal workup and purification, the desired
1-substituted imidazoles were often isolated in solid form in 84–95% yields and no 1,3-disubstituted
imidazolium salts were detected (see Scheme 1 and Table 1, 1b–9b). The application of this method to
N-(bromomethyl)phthalimide (10a) and 2-(bromomethyl)tetrahydro-2H-pyran (11a) also gave the
corresponding products (10b and 11b) in 85% and 75% yields without the formation of 1,3-disubstituted
imidazolium salts (see Table 1).
Under the same conditions, bromoacetaldehyde ethylene acetal (12a) reacted with lithium imidazolide to
give the mono-substituted products (12b) in 73% yield. The lower yields of 11a and 12a come from the
weak stability of acetal and tetrahydropyran moieties for α-carbocation.12

HETEROCYCLES, Vol. 68, No. 7, 2006
1361
O
N
Lithium Imidazole
N
N
O
1b
1c
Br
O
O
O
Imidazole
N
N
Br
N
+
1a
1b
Scheme 1
X
O
O
O
X
X
EtO
MeO
HO
1a. X = Br
2a. X = Br
3a. X = Br
1b. X= imidazolyl
1c. 1,3-disubstituted
imidazolium salts
2b. X = imidazolyl
2c. 1,3-disubstituted
imidazolium salts
3b. X = imidazolyl
3c. 1,3-disubstituted
imidazolium salts
O
O
O
X
Y
X
X
4a. X = Br, Y = Me
4b. X = imidazolyl
4c. 1,3-disubstituted
imidazolium salts
5a. X = Br, Y = OMe
5b. X = imidazolyl
5c. 1,3-disubstituted
imidazolium salts
8a. X = Br
8b. X = imidazolyl
8c. 1,3-disubstituted
imidazolium salts
9a. X = Br
7a. X = Br, Y = Phenyl
7b. imidazolyl
7c.1,3-disubstituted
imidazolium salts
6a. X = Br, Y = NO2
6b. X = imidazolyl
6c. 1,3-disubstituted
imidazolium salts
9b. X = imidazolyl
9c. 1,3-disubstituted
imidazolium salts
O
X
N
X
O
O
X
O
O
11a. X = Br
12a. X = Br
10a. X = Br
11b. X = imidazolyl
11c. 1,3-disubstituted
imidazolium salts
12b. X = imidazolyl
10b. X = imidazolyl
10c. 1,3-disubstituted
imidazolium salts
12c. 1,3-disubstituted
imidazolium salts
Chart 1
In control experiments, α-bromoketones (1a–10a) were treated with the excess amount of imidazole by
employing the published method.8 However, the reaction gave a mixture of 1-substituted imidazoles and
1,3-disubstituted imidazolium salts (see Table 1). The yields of 1-substituted imidazoles by this method
were thus lower than that by using lithium imidazolide as the reactant. Only in the case of
2-(bromomethyl)tetrahydro-2H-pyran (11a) and bromoacetaldehyde ethylene acetal (12a) gave the

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desired products exclusively (74% and 72% yields).The yields of the reactions in the control experiments
were consistent with the data reported in literature.13,14
Table 1. α-Bromoketones and bromometyl compounds reacted with lithium imidazolide or imidazole.
Lithium imidazolide
Imidazole
Product
Substrate
Yield
1-Substituted
imidazoles
Reaction
time (h)
a
Yield
Yield
1-Substituted
imidazoles
1,3-Disubstituted
imidazolium salts
(%)
a
a
(%)
(%)
1a
2a
1b
2b
97
88
91
88
95
84
96
92
95
85
75
73
4
4
1b
2b
30
40
45
43
40
31
37
32
34
39
74
72
1c
2c
54
37
35
39
49
60
60
64
52
40
3a
3b
10
3
3b
3c
4a
4b
4b
4c
5a
5b
3
5b
5c
6a
6b
3
6b
6c
7a
7b
12
12
12
3
7b
7c
8a
8b
8b
8c
9a
9b
9b
9c
10a
11a
12a
10b
11b
12b
10b
11b
12b
10c
11c
12c
b
> 12
> 12
-
b
-
a
b
The yield was provided by the column separation.
Non-detectable.
This newly developed reaction proceeded in 0 °C and the reaction time was around 2.0 h, which was
easily performed in laboratory and industry. The use of sodium imidazolide as the reactant was also tried
and found to give the products in slightly lower yields compared with the use of lithium imidazolide.
Nevertheless, the reaction gave more impurities and the preparation of sodium imidazolide required more
attention. The new method was also applicable for large-scale synthesis and the undesired di-substituted
by-products were also not formed. In example, compound (3a) could be prepared up to kilogram scale

HETEROCYCLES, Vol. 68, No. 7, 2006
1363
(3.11 Kg of 3a, see EXPERIMENTAL section) and column chromatography was not necessary.
The described method successfully provided a convenient and efficient preparation of 1-substituted
imidazoles. The undesired di-substituted imidazole by-product was not found in this reaction. This
method could also be applicable to large-scale industrial preparation of the 1-substituted imidazoles.
EXPERIMENTAL
All chemicals were reagent grade and used as purchased. All reactions were carried out under nitrogen
atmosphere and monitored by TLC. Flash column chromatography was carried out on silica gel (230-400
mesh). Commercially available reagents were used without further purification unless otherwise noted.
Ethyl acetate and hexanes were purchased from Mallinckrodt Chemical Co. Dry THF (reagent grade) was
purchased from Aldrich. The following compounds were purchased from Aoros Chemical Co:
2-bromo-2-acetonaphinone,
1-(bromoacetyl)pyrene,
α-bromo-4-methoxyacetophenone,
N-bromomethylphthalimide,
α-bromo-4-methylacetophenone,
2-bromomethyl-1,3-dioxolane,
2-bromomethyltetrahydro-2H-pyran, α-bromo-4-nitroacetophenone, 1-bromo-3,3-dimethylbutan-2-one,
α -bromo-4-phenylacetophenone, ethyl 2-bromoacetate. Analytical thin-layer chromatography (TLC) was
performed on precoated plates (silica gel 60 F-254), purchased from Merck Inc. Mixtures of AcOEt and
hexane were used as eluants. Purification by gravity column chromatography was carried out by use of
Merck Reagents Silica Gel 60 (particle size 0.063–0.200 mm, 70–230 mesh ASTM). Infrared (IR) spectra
were measured on a Bomem Michelson Series FT-IR spectrometer. The wavenumbers reported are
referenced to the polystyrene 1601 cm–1 absorption. Absorption intensities are recorded by the following
abbreviations: s, strong; m, medium; w, weak. Proton NMR spectra were obtained on a Bruker (300
MHz) spectrometer by use of chloroform-d/ DMSO–d6 as solvent. Carbon-13 NMR spectra were obtained
on a Bruker (75 MHz) spectrometer by used of chloroform-d as solvent. Carbon-13 chemical shifts are
referenced to the center of the CDCl3 triplet (δ 77.0 ppm). Multiplicities are recorded by the following
abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; J, coupling constant (hertz).
Elemental analyses were carried out on a Heraeus CHN–O RAPID element analyzer.
Standard procedure for the formation of 1-substituted imidazoles: A solution of imidazole (3.0
equiv) in THF was added with lithium hydride (3.1 equiv) and heated to reflux for 30 min under N2.
α-Bromoketones (1a–9a), N-(bromomethyl)phthalimide (10a), 2-(bromomethyl)tetrahydro-2H-pyran
(11a), or bromoacetaldehyde ethylene acetal (12a, 1.0 equiv) in THF was slowly added to the reaction
mixture at –5–0 °C for 5.0 min under N2. After the reaction was completed, the reaction mixture was
quenched and washed by a saturated NH4Cl aqueous solution in ice-bath. The organic layer was
concentrated under reduced pressure and the residue was purified by gravity column chromatography on

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silica gel or recrystallization to provide the desired 1-substituted imidazoles (1b–12b).
Compound (1b): TLC Rf 0.61 (10% MeOH in CH2Cl2); 1H NMR (DMSO–d6, 300 MHz) δ 1.16 (s, 9 H, 3
× CH3), 5.22 (s, 2 H, CH2), 6.86 (s, 1 H, imd-H), 6.97 (s, 1 H, imd-H), 7.46 (s, 1 H); 13C NMR (DMSO-d6,
75 MHz) δ 26.68, 43.51, 51.63, 121.52, 128.62, 139.03, 209.90; IR (diffuse reflectance) 3616 (m), 3114
(m), 2970 (s), 1719 (s, C=O), 1510 (m), 1479 (m), 1368 (m), 1290 (m), 1235 (m), 1064 (s), 1037 (m), 914
(m), 825 (m), 743 (m), 713 (m), 662 (m), 568 (m) cm–1; FABMS m/z (relative intensity) 167 (M + 1, 100),
83 (3), 82 (13), 81 (8), 73 (11), 69 (11), 57 (16), 55 (3).
1
Compound (2b): TLC Rf 0.60 (10% MeOH in CH2Cl2); mp 121–123 °C; H NMR (DMSO–d6, 300
MHz) δ 1.13–1.22 (t, 3 H, J = 6.0 Hz, CH3), 4.02–4.17 (q, 2 H, J = 6.0 Hz, OCH2), 4.93 (s, 2 H, CH2),
6.87 (s, 1 H, imd-H), 7.12 (s, 1 H, imd-H), 7.59 (s,1 H, imd-H); 13C NMR (DMSO-d6, 75 MHz) δ 14.41,
47.53, 61.46, 121.05, 128.47, 138.59, 168.95; IR (diffuse reflectance) 3117 (m), 2934 (m), 1681 (m,
C=O), 1600 (m) 1574 (m), 1508 (m), 1459 (m), 1420 (m), 1359 (m), 1308 (m),1169 (m), 1111 (m), 991
(m), 907 (m), 836 (m), 818 (m), 793 (m), 718 (m) cm–1; FABMS m/z (relative intensity) 155 (M + 1, 100),
154 (15), 137 (10), 136 (14), 127 (32), 107 (9), 95 (13), 91 (13), 83 (14), 81 (19), 77 (15), 71 (18), 67
(18).
1
Compound (3b): mp 196–198 °C; H NMR (CDCl3, 400 MHz) δ 0.66 (s, 3 H, 19-CH3), 076 (s, 3 H,
18-CH3), 0.78–1.05 (m, 2 H), 1.16–1.71 (m, 18 H), 1.92–1.97 (m, 1 H), 2.14–2.29 (m, 1 H), 2.57 (t, 3 H,
J = 9.0 Hz, 17α-CH), 3.18 (s, 2 H, –OCH2), 3.39 (s, 3 H, –OCH3), 4.50 (d, 1 H, J = 18.0 Hz, –CHBr),
13
4.71 (d, 1 H, J = 18.0 Hz, –CHBr), 6.85 (s, 1 H), 7.09 (s, 1 H), 7.41 (s, 1 H); C NMR (CDCl3, 100
MHz) δ 12.31, 13.88, 21.27, 23.25, 24.49, 28.54, 31.46, 31.98, 35.52, 35.54, 37.03, 38.12, 39.28, 44.84,
45.11, 54.14, 56.49, 56.78, 60.47, 71.06, 119.95, 129.41, 137.79, 203.19; IR (diffuse reflectance) 3483 (s),
2905 (s), 1754 (m, C=O), 1531 (m), 1446 (m), 1372 (m), 1265 (m), 1050 (m), 988 (m), 887 (m), 824 (m),
722 (m), 634 (m), 502 (m) cm–1; MS m/z (relative intensity) 429 (M+, 100), 427 (31), 413 (15), 411 (22),
383 (22), 137 (28), 105 (13), 93 (12), 82 (37), 69 (39); HRMS calcd for C26H40N2O3 428.3039, found
428.3037.
Compound (4b): TLC Rf 0.38 (10% MeOH in CH2Cl2); mp 136–138 °C; 1H NMR (DMSO–d6, 300
MHz) δ 2.35 (s, 3 H), 5.69 (s, 2 H, CH2), 6.91 (s, 1 H, imd-H), 7.10 (s, 1 H, imd-H), 7.39 (d, 2 H, J = 3.2
Hz, Ar-H), 7.57 (s, 1 H, imd-H), 7.93 (d, 2 H, J = 3.2 Hz, Ar-H); 13C NMR (DMSO-d6, 75 MHz) δ 21.65,
52.88, 121.37, 128.11, 128.47, 129.85, 132.37, 138.73, 144.86, 193.47; IR (diffuse reflectance) 3117 (m),
2933 (m), 1681 (m, C=O), 1603 (m), 1508 (m), 1441 (m), 1420 (m), 1348 (m), 1230 (m), 1110 (m), 991
(m), 907 (m), 816 (m), 793 (m), 718 (m) cm–1; FABMS m/z (relative intensity) 201 (M + 1, 59), 147 (7),
131 (6), 119 (12), 117 (6), 115 (7), 105 (13), 91 (19), 83 (6), 79 (6), 77 (8), 71 (6), 69 (31), 67 (6).
Compound (5b): TLC Rf 0.31 (10% MeOH in CH2Cl2); mp 171–172 °C; 1H NMR (CDCl3, 300 MHz) δ
3.88 (s, 3 H, OCH3), 5.33 (s, 2 H, CH2), 6.93 (s, 1 H, imd-H), 6.97 (d, 2 H, J = 6.2 Hz, ArH), 7.11 (s, 1 H,

HETEROCYCLES, Vol. 68, No. 7, 2006
1365
imd-H), 7.51 (s, 1 H, imd-H), 7.94 (d, 2 H, J = 6.2 Hz, ArH); 13C NMR (CDCl3, 75 MHz) δ 52.13, 55.57,
114.24, 120.33, 127.08, 129.12, 130.30, 138.10, 164.38, 189.98; IR (diffuse reflectance) 3397 (m), 2934
(m), 1687 (m, C=O), 1601 (m), 1509 (m), 1461 (m), 1350 (m), 1308 (m), 1260 (m), 1168 (m), 1081 (m),
1008 (m), 988 (m), 906 (m), 830 (m), 792 (m), 775 (m), 717 (m) cm–1; FABMS m/z (relative intensity)
217 (M + 1, 100), 136 (19), 135 (47), 121 (39), 91 (21), 81 (23), 77 (32), 73 (21), 69 (42), 57 (44), 55
(43), 53 (10).
Compound (6b): TLC Rf 0.28 (10% MeOH in CH2Cl2); mp 164–166 °C; 1H NMR (DMSO–d6, 300
MHz) δ 5.79 (s, 2 H, CH2), 6.92 (s, 1 H, imd-H), 7.11 (s, 1 H, imd-H), 7.58 (s, 1 H, imd-H), 8.24 (d, 2 H,
J = 3.2 Hz, ArH), 8.39 (d, 2 H, J = 3.2 Hz, ArH); 13C NMR (DMSO-d6, 75 MHz) δ 53.48, 121.24, 123.70,
124.28, 127.37, 129.76, 130.78, 135.12, 193.12; IR (diffuse reflectance) 3040 (m), 1714 (s, C=O), 1600
(m), 1527 (m), 1355 (m), 1287 (m), 1106 (m), 1036 (m), 991 (m), 856 (m), 743 (m), 507 (m) cm–1;
FABMS m/z (relative intensity) 232 (M + 1, 51), 154 (40), 149 (24), 107 (27), 105 (20), 97 (26), 95 (32),
91 (35), 86 (100), 79 (25), 77 (26), 71 (27), 69 (67), 67 (33).
Compound (7b): TLC Rf 0.31 (6% MeOH in CH2Cl2); mp 195–197 °C; 1H NMR (DMSO–d6, 300
MHz) δ 5.77 (s, 2 H, CH2), 6.92 (s, 1 H, imd-H), 7.13 (s, 1 H, imd-H), 7.34–7.55 (m, 3 H , ArH), 7.60 (s,
1 H, imd-H), 7.78 (d, 2 H, J = 3.1 Hz, Ar-H), 7.90 (d, 2 H, J = 3.1 Hz, ArH), 8.11 (d, 2 H, J = 3.1 Hz,
13
ArH); C NMR (DMSO-d6, 75 MHz) δ 52.48, 120.81, 126.93, 127.77, 128.46, 128.61, 129.04, 129.51,
133.18, 138.24, 138.58, 145.05, 193.07; IR (diffuse reflectance) 3386 (m), 2933 (m), 1681 (m, C=O),
1601 (m), 1574 (m), 1441 (m), 1420 (m), 1358 (m), 1267 (m), 1170 (m), 1081 (m), 1039 (m), 991 (m),
907 (m), 834 (m), 818 (m), 743 (m), 719 (m) cm–1; FABMS m/z (relative intensity) 263 (M + 1, 36), 181
(20), 154 (38), 137 (25), 136 (35), 91 (24), 90 (22), 89 (33), 81 (32), 79 (25), 78 (22), 77 (53), 73 (45), 71
(25).
Compound (8b): TLC Rf 0.43 (6% MeOH in CH2Cl2); mp 1226–228 °C; 1H NMR (DMSO–d6, 300
MHz) δ 5.90 (s, 2 H, CH2), 6.97 (s, 1 H, imd-H), 7.19 (s, 1 H, imd-H), 7.67–7.75 (m, 3 H , ArH),
8.05–8.19 (m, 4 H , ArH), 8.81 (s, 1H, imd-H); 13C NMR (DMSO-d6, 75 MHz) δ 52.62, 120.95, 123.32,
127.19, 127.79, 127.90, 128.55, 128.98, 129.58, 130.01, 131.75, 132.09, 135.30, 138.38, 193.51; IR
(diffuse reflectance) 3114 (m), 2922 (m), 1693 (s, C=O), 1505 (m), 1218 (m), 1187 (m), 1080 (m), 993
(m), 914 (m), 861 (m), 746 (m), 706 (m), 590 (m), 476 (m) cm–1; FABMS m/z (relative intensity) 237 (M
+ 1, 27), 155 (60), 154 (100), 141 (27), 138 (35), 137 (61), 136 (93), 127 (29), 107 (38), 91 (32), 89 (41),
77 (49), 55 (48).
Compound (9b): TLC Rf 0.54 (10% MeOH in CH2Cl2); mp 279–281 °C; 1H NMR (DMSO–d6, 300
MHz) δ 5.94 (s, 2 H, CH2), 7.00 (s, 1 H, imd-H), 7.28 (s, 1 H, imd-H), 7.83 (s, 1 H, imd-H), 8.13 (t, 1 H,
J = 9.0 Hz, ArH), 8.24–8.43 (m, 7 H, ArH), 8.72 (d, 1 H, J = 3.0 Hz, ArH), 8.87 (d, 1 H, J = 3.0 Hz,
13
ArH); C NMR (DMSO-d6, 75 MHz) δ 55.16, 121.44, 123.71, 124.45, 124.78, 126.78, 127.36, 127.56,

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HETEROCYCLES, Vol. 68, No. 7, 2006
128.31, 129.39, 130.30, 130.99, 134.21, 138.88, 197.55; ; IR (diffuse reflectance) 3431 (m), 2930 (m),
1680 (m, C=O), 1594 (m), 1510 (m), 1384 (m), 1217 (m), 1122 (m), 994 (m), 847 (m), 757 (m) cm–1;
FABMS m/z (relative intensity) 311 (M + 1, 17), 229 (10), 215 (10), 201 (6), 155 (12), 154 (41), 138 (16),
137 (30), 136 (34), 107 (14), 91 (17), 89 (22), 81 (23), 77 (35), 71 (26).
Compound (10b): TLC Rf 0.45 (60% EtOAc in Hexane); mp 185–187 °C; 1H NMR (DMSO–d6, 300
MHz) δ 5.81 (s, 2 H, CH2), 6.94 (s, 1 H, imd-H), 7.22 (s, 1 H, imd-H), 7.81 (s, 1 H, imd-H), 7.83–8.01 (m,
13
4 H , ArH); C NMR (DMSO-d6, 75 MHz) δ 47.38, 119.72, 124.03, 129.29, 131.53, 135.37, 138.05,
167.31; IR (diffuse reflectance) 2923 (m), 1716 (s, C=O), 1457 (m), 1117 (m), 1100 (m), 1030 (m), 952
–1
+
(m), 822 (m), 664 (m), 530 (m) cm ; FABMS m/z (relative intensity) 228 (M + 1, 100), 227 (M , 4), 161
(8), 160 (66), 154 (10), 149 (5), 138 (5), 136 (11), 69 (9).
Compound (11b): TLC Rf 0.68 (8% MeOH in CH2Cl2); 1H NMR (DMSO–d6, 300 MHz) δ 1.21–1.79 (m,
6 H), 3.31–3.62 (m, 4 H), 3.87–3.96 (m, 1 H) 7.10 (s, 2H, imd-H), 7.82 (s, 1H, imd-H); 13C NMR
(DMSO-d6, 75 MHz) δ 22.58, 25.30, 29.64, 37.11, 67.59, 76.22, 121.44, 135.11; IR (diffuse reflectance)
3366 (m), 3139 (m), 1593 (m), 1506 (m), 1258 (m), 1177 (m), 1047 (m), 986 (m), 838 (m), 757 (m), 632
(m) cm–1; FABMS m/z (relative intensity) 167 (M + 1, 100), 137 (4), 82 (5), 81 (7), 69 (85), 67 (7), 57
(12), 55 (21).
Compound (12b): TLC Rf 0.60 (8% MeOH in CH2Cl2); 1H NMR (DMSO–d6, 300 MHz) δ 3.68 (t, 4 H , J
= 6.0 Hz, OCH2), 4.04 (d, 2 H, J = 3.0 Hz, CH2), 4.98 (t, 1 H, J = 3.0 Hz, OCH), 6.77 (s, 1 H, imd-H),
7.02 (s, 1 H, imd-H), 7.47 (s, 1 H, imd-H); 13C NMR (DMSO-d6, 75 MHz) δ 48.80, 65.05, 101.68, 120.90,
128.38, 138.47; IR (diffuse reflectance) 3115 (m), 2894 (m), 1698 (m), 1506 (m), 1393 (m), 1287 (m),
1234 (m), 1143 (s), 1079 (m), 946 (m), 747 (m), 663 (m), 491 (m) cm–1; FABMS m/z (relative intensity)
155 (M + 1, 31), 154 (33), 149 (40), 14 (60), 133 (56), 119 (56), 117 (78), 109 (52), 105 (60), 97 (54), 95
(82), 91 (79), 83 (73), 81 (100), 79 (69) , 77 (57).
The Scale-up procedure of 3α-Hydroxy-21-(1’-imidazolyl)-3β-methoxymethyl-5α-pregnan-20-one
(3b): To a solution of imidazole (2.31 kg, 21.7 mol, 3.0 equiv) in THF (20 L) was added lithium hydride
(0.179 kg, 22.4 mol, 3.1 equiv). The solution was heated at reflux for 30 min under N2. Compound (3a)
(3.11 kg, 7.28 mol, 1.0 equiv) in THF (10 L) was slowly added to the reaction mixture at –5–0 °C in a
period of 0.5–1 h under N2. The reaction solution was maintained at –5–0 °C and stirred for 2.0 h. When
the reaction completed, the reaction mixture was quenched by saturated NH4Cl aqueous solution (10 L) in
ice-bath. The organic layer was separated and concentrated under reduced pressure to give pure 3b (2.84
kg, 6.62 mol) as white powder in 91% isolated yield.
Standard procedure for the formation of 1-substituted imidazoles and 1,3-disubstituted

HETEROCYCLES, Vol. 68, No. 7, 2006
1367
imidazolium salts: A solution of α-bromoketones (1a–9a, 1.0 equiv) or N-(bromomethyl)phthalimide
(10a), 2-(bromomethyl)-tetrahydro-2H-pyran (11a, 1.0 equiv), or bromoacetaldehyde ethylene acetal (12a,
1.0 equiv) with imidazole (3.0 equiv) in THF was heated at reflux for 8–24 h under N2. When the reaction
was completed, the reaction mixture was concentrated to remove THF and the resulting oil was
redissolved in CH2Cl2. The solution was washed with 5% aqueous NaHCO3 solution and brine. The
organic layer was dried over MgSO4(s), filtered, and concentrated under reduced pressure. The residue
was purified by gravity column chromatography on silica gel or recrystallization to provide the
corresponding 1-substituted imidazoles (1b–12b) and 1,3-disubstituted imidazolium salt (1c–10c).
Compound (1c): TLC Rf 0.23 (10% MeOH in CH2Cl2); mp 81–82 °C; 1H NMR (DMSO–d6, 300 MHz) δ
1.19 (s, 18 H, 6 × CH3), 5.74 (s, 4 H, 2 × CH2), 7.71 (d, 2 H, J = 6.1 Hz, imd-H), 9.00 (s, 1 H, imd-H);
13C NMR (DMSO-d6, 75 MHz) δ 26.15, 43.04, 54.54, 121.52, 123.67, 138.63, 207.54; IR (diffuse
reflectance) 3454 (m), 3144 (m), 3059 (m), 2970 (m), 1723 (s, C=O), 1563 (m), 1463 (m), 1368 (m),
1266 (m), 1176 (m), 1035 (m), 1009 (m), 940 (m), 839 (m), 781 (m), 628 (m), 580 (m) cm–1; FABMS m/z
(relative intensity) 266 (M + 1, 18), 265 (100), 180 (19), 167 (27), 154 (18), 137 (15), 136 (22), 107 (13),
95 (28), 91 (17), 85 (16), 83 (24), 81 (25), 79 (13).
Compound (2c): TLC Rf 0.17 (10% MeOH in CH2Cl2); 1H NMR (CDCl3, 300 MHz) δδ 1.25–1.30 (t, 6 H,
J = 6.0 Hz, 2 × CH3), 4.20–4.27 (q, 4 H, J = 6.0 Hz, 2 × OCH2), 4.93 (s, 2 H, CH2), 7.67 (d, 2 H, J = 9.2
13
Hz, imd-H), 9.88 (s, 1 H, imd-H); C NMR (CDCl3, 75 MHz) δ 14.03, 50.49, 62.95, 123.45, 138.74,
166.12; IR (diffuse reflectance) 3392 (m), 2933 (m), 1728 (m, C=O), 1601 (m), 1508 (m), 1459 (m), 1376
(m), 1348 (m), 1169 (m), 1111 (m), 1021 (m), 992 (m), 877 (m), 828 (m), 818 (m), 793 (m), 718 (m)
cm–1; FABMS m/z (relative intensity) 256 (M + 1, 1), 255 (6), 241 (66), 213 (70), 185 (26), 168 (20), 155
(100), 127 (32), 81 (19), 69 (30).
1
Compound (3c): H NMR (CDCl3 + MeOD-d, 400 MHz) δ 0.66 (s, 6 H, 19-CH3), 073 (s, 6 H, 18-CH3),
0.75–1.09 (m, 4 H), 1.12–1.92 (m, 36 H), 2.01–2.23 (m, 4 H), 271 (t, 2 H, J = 8.8 Hz, 17-CH), 3.36 (s, 4
H, OCH2), 3.36 (s, 6 H, OCH3), 5.19 (d, 2 H, J = 18.4 Hz, CHBr), 5.49 (d, 2 H, J = 18.4 Hz, CHBr), 7.28
(s, 1 H), 7.32 (s, 1 H), 9.30 (s, 1 H); IR (diffuse reflectance) 3426 (s), 2931 (s), 1731 (m, C=O), 1632 (m),
1569 (m)1449 (m), 1385 (m), 1352 (m), 1294 (m), 1172 (m), 1119 (m), 1040 (m), 961 (m), 926 (m), 900
-1
+
(m), 845 (m), 809 (m), 745 (m), 720 (m), 690 (m), 624 (m) cm ; MS m/z (relative intensity) 789 (M ,
100), 773 (14), 744 (12), 673 (2), 605 (3), 551 (3), 497 (17), 429 (31), 442 (20), 383 (2), 315 (3), 281 (2),
207 (3), 149 (14), 137 (10), 81 (11), 73 (23), 69 (12); HRMS calcd for C49H77N2O6 789.5776, found
789.5771.
1
Compound (4c): TLC Rf 0.15 (10% MeOH in CH2Cl2); mp 239–241 °C; H NMR (DMSO–d6, 300
MHz) δ 2.42 (s, 6 H, 2 × CH3), 6.15 (s, 4 H, 2 × CH2), 7.44 (d, 4H, J = 3.1 Hz, ArH), 7.80 (s, 2 H, imd-H),
13
7.97 (d, 4 H, J = 3.1 Hz, ArH), 9.10 (s, 1 H, imd-H); C NMR (DMSO-d6, 75 MHz) δ 21.73, 55.89,

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HETEROCYCLES, Vol. 68, No. 7, 2006
124.10, 128.68, 130.03, 131.66, 138.97, 145.58, 191.21; IR (diffuse reflectance) 3393 (m), 3117 (m),
2933 (m), 1963 (m), 1728 (m, C=O), 1681 (m), 1573 (m), 1508 (m), 1441 (m), 1420 (m), 1358 (m), 1309
(m), 1169 (m), 1111 (m), 1021 (m), 992 (m), 877 (m), 828 (m), 793 (m), 775 (m), 718 (m) cm–1; FABMS
+
m/z (relative intensity) 334 (M + 1, 7), 333 (M , 29), 201 (7), 154 (28), 137 (21), 136 (29), 119 (29), 107
(21), 105 (25), 95 (26), 91 (33), 89 (22), 83 (27), 81 (32), 79 (22), 77 (32).
1
Compound (5c): TLC Rf 0.15 (10% MeOH in CH2Cl2); mp 258–260 °C; H NMR (DMSO–d6, 300
MHz) δ 3.87 (s, 6 H, 2 × OCH3), 6.07 (s, 4 H, 2 × CH2), 7.14 (d, 4H, J = 6.1 Hz, ArH), 7.75 (s, 2 H,
13
imd-H), 8.03 (d, 4 H, J = 6.1 Hz, Ar-H), 9.05 (s, 1 H, imd-H); C NMR (DMSO–d6, 75 MHz) δ 56.06,
56.65, 115.23, 124.55, 127.43, 131.47, 139.47, 164.99, 190.40; IR (diffuse reflectance) 3460 (m), 3109
(m), 1723 (m, C=O), 1601 (m), 1573 (m), 1511 (m), 1467 (m), 1351 (m), 1309 (m), 1262 (m), 1218 (m),
1120 (m), 1089 (m), 1025 (m), 988 (m), 956 (m), 845 (m), 799 (m), 785 (m), 710 (m) cm–1; FABMS m/z
+
(relative intensity) 366 (M + 1, 9), 365 (M , 37), 230 (6), 217 (13), 215 (3), 176 (2), 169 (2), 168 (2), 167
(5), 166 (3), 165 (5), 164 (2), 163 (2).
1
Compound (6c): TLC Rf 0.15 (10% MeOH in CH2Cl2); mp 214–216 °C; H NMR (DMSO–d6, 300
MHz) δ 6.19 (s, 4 H, 2 × CH2), 7.78 (s, 2 H, imd-H), 8.29 (d, 4 H, J = 2.9 Hz, ArH), 8.45 (d, 4 H, J = 2.9
Hz, ArH), 9.06 (s, 1 H, imd-H); 13C NMR (DMSO-d6, 75 MHz) δ 46.00, 120.23, 123.90, 124.22, 129.71,
130.89, 134.72, 190.9; IR (diffuse reflectance) 3371 (m), 3110 (m), 1704 (s, C=O), 1602 (m), 1519 (m),
1348 (m), 1176 (m), 1089 (m), 993 (m), 857 (m), 756 (m), 748 (m), 685 (m), 571 (m) cm–1; FABMS m/z
+
(relative intensity) 396 (M + 1, 2), 395 (M , 9), 245 (3), 222 (3), 191 (4), 185 (5), 154 (3), 149 (5), 136
(6), 107 (4), 102 (13), 97 (5), 91 (9), 89 (4).
Compound (7c): TLC Rf 0.12 (6% MeOH in CH2Cl2); mp 254–256 °C; 1H NMR (DMSO–d6, 300 MHz)
δ 6.21 (s, 4 H, 2 × CH2), 7.46–7.58 (m, 6 H, ArH), 7.82 (d, 2 H, J = 3.0 Hz, ArH), 7.83 (s, 1 H, imd-H),
7.99 (d, 4 H, J = 3.0 Hz, ArH), 8.18 (d, 4 H, J = 3.0 Hz, ArH), 9.14 (s, 1 H, imd-H); 13C NMR (DMSO-d6,
75 MHz) δ 56.07, 124.18, 127.51, 129.15, 129.34, 129.60, 132.98, 138.95, 139.03, 146.10, 191.32; IR
(diffuse reflectance) 3349 (m), 3118 (m), 2933 (m), 1681 (m, C=O), 1601 (m), 1508 (m), 1459 (m), 1359
(m), 1309 (m), 1232 (m), 1111 (m), 1022 (m), 992 (m), 837 (m), 743 (m), 718 (m) cm–1; FABMS m/z
(relative intensity) 458 (M + 1, 35), 457 (100), 392 (7), 307 (16), 289 (11), 263 (7), 181 (13), 167 (19).
Compound (8c): TLC Rf 0.17 (6% MeOH in CH2Cl2); mp 261–263 °C; 1H NMR (DMSO–d6, 300 MHz)
δ 6.30 (s, 4 H, 2 × CH2), 7.67–7.77 (m, 4 H, ArH), 7.85 (s, 2 H, ArH), 8.05–8.21 (m, 8 H, ArH), 8.83 (s, 2
H, imd-H), 9.16 (s, 1 H, imd-H); 13C NMR (DMSO-d6, 75 MHz) δ 56.14, 123.68, 124.31, 127.90, 128.36,
129.27, 129.82, 130.13, 130.93, 131.52, 132.50, 135.99, 139.16, 191.69; IR (diffuse reflectance) 3439
(m), 3044 (m), 2956 (m), 1693 (m, C=O), 1455 (m), 1361 (m), 1171 (m), 1095 (m), 995 (m), 908 (m),
854 (m), 766 (m), 727 (m), 645 (m), 468 (m) cm–1; FABMS m/z (relative intensity) 406 (M + 1, 3), 405

HETEROCYCLES, Vol. 68, No. 7, 2006
1369
+
(M , 9), 391 (3), 237 (8), 167 (55), 155 (43), 154 (97), 149 (55), 138 (39), 137 (73), 136 (98), 107 (43),
91 (38), 89 (50), 77(60).
1
Compound (9c): TLC Rf 0.24 (10% MeOH in CH2Cl2); mp 329–331 °C; H NMR (DMSO–d6, 300
MHz) δ 6.53 (s, 4 H, 2 × CH2), 8.09 (s, 2 H, imd-H), 8.16–8.51 (m, 16 H , ArH), 8.89 (d, 2 H, J = 5.8 Hz,
13
ArH), 9.09 (d, 2 H, J = 5.8 Hz, ArH), 9.47 (s, 1 H, imd-H); C NMR (DMSO-d6, 75 MHz) δ 57.83,
123.52, 124.37, 124.62, 124.84, 126.97, 127.36, 127.49, 127.99, 129.81, 130.14, 130.58, 130.69, 130.88,
134.74, 194.43; IR (diffuse reflectance) 3384 (m), 3043 (m), 1682 (m, C=O), 1593 (m), 1508 (m), 1382
(m), 1221 (m), 1121 (m), 961 (m), 849 (m), 761 (m), 718 (m) cm–1; FABMS m/z (relative intensity) 556
(M + 1, 7), 555 (13), 554 (55), 553 (100), 391 (29), 311 (30), 307 (51), 289 (39), 229 (41), 215 (74), 202
(26), 201 (33).
1
Compound (10c): TLC Rf 0.10 (60% EtOAc in Hexane); mp 297–299 °C; H NMR (DMSO–d6, 300
MHz) δ 6.01 (s, 4 H, 2 × CH2), 7.78 (s, 2 H, imd-H), 7.89–7.98 (m, 8 H , ArH), 9.42 (s, 1 H, imd-H); 13C
NMR (DMSO-d6, 75 MHz) δ 50.06, 122.95, 124.21, 131.77, 135.54, 137.85, 167.09; IR (diffuse
reflectance) 3457 (m), 1723 (s, C=O), 1544 (m), 1469 (m), 1355 (m), 1292 (m), 1146 (m), 1024 (m), 955
–1
+
(m), 853 (m), 710 (m) cm ; FABMS m/z (relative intensity) 388 (M + 1, 2), 387 (M , 8), 229 (15), 228
(100), 161 (11), 160 (89), 154 (17), 149 (8).
ACKNOWLEDGEMENTS
We are grateful to the National Science Council of Rpublic of China for financial support.
REFERENCES
1
2
H. Vanden Bossche, J. Steroid Biochem. Molec. Biol., 1992, 42, 45.
S. K. Thompson, K. H. M. Murthy, B. Zhao, E. Winborne, D. W. Green, S. M. Fisher, R. L.
DesJarlais, T. A. Jr. Tomaszek, T. D. Meek, J. G. Gleason, and S. S. Abdel-Meguid, J. Med. Chem.,
1994, 37, 3100.
3
4
(a) F. T. Boyle and G. F. Costello, Chem. Soc. Rev., 1998, 27, 251. (b) V. C. O. Njar and A. M.
H.Brodie, Drugs, 1999, 58, 233.
D. H. Blackenhorm, S. A. Nission, R. L. Johson, M. E. Sanmarco, S. P. Azen, and L.
Cashin-Hemphill, J. Am. Med. Assoc., 1987, 257, 3233.
5
6
7
R. Howe, Adv. Drug Res., 1974, 9, 7.
V. C. O. Njar, Synthesis, 2000, 14, 2019.
F. F. Wong, C.-Y. Chen, T.-H. Chen, J.-J Huang, H.-P. Fang, and M.-Y. Yeh, Steroids, 2006, 71,
77.

1370
HETEROCYCLES, Vol. 68, No. 7, 2006
8
9
(a) C. D. Jones, M. A. Winter, K. S. Hirsch, N. Stamm, H. M. Talyor, H. E. Holden, J. D. Davenport,
E. V. Krumkalns, and R. G. Suhr, J. Med. Chem., 1990, 33, 416. (b) D. M. Rotstein, D. J. Kertesz,
K. A. M. Walker, and D. C. Swinney, J. Med. Chem., 1992, 35, 2818.
(a) M. R. Grimmett, In Advances in Hteterocyclic Chemistry; Vol. 12, ed. by A. R. Katriztky and A.
J. Boulton, Academic Press, New York, 1970, pp. 162–166. (b) M. Häring, Helev. Chim. Acta, 1959,
42, 1845. (c) Sankyo, Japan Kokai 51-105060. Chem. Abstr., 1977, 86, 155649t.
10 K. Yamauchi and M. Kinoshita, J. Chem. Soc., Perkin Trans. 1., 1973, 2506.
11 T. Kamijo, Y. Yamamoto, H. Harada, and K. Iizuka, Chem. Pharm. Bull., 1983, 31, 1213.
12 H. J. J. Loozen, J. J. M. Drouen, and O. Piepers, J. Org. Chem., 1975, 40, 3279.
13 J. Heeres and J. V. Cutsem, J. Med. Chem., 1981, 24, 1360.
14 J. G. Cannon, M. F. Sahin, R. K. Bhatnagar, J. R. Flynn, and J. P. Long, J. Med. Chem., 1991, 34,
1582.